Treatment protocol generation for diseases related to angiogenesis

Abstract

A computer-implemented method for determining an optimal treatment protocol for a disease related to angiogenesis, comprising creating an angiogenesis model including pro-angiogenic and anti-angiogenic factors. Effective vessel density (EVD) is incorporated as a factor regulating switching on and switching off of at least one component in the angiogenesis model. Effects of vasculature maturation and mature vessel destabilization are incorporated. Pro-angiogenic and anti-angiogenic factors, which can influence changes in state of a tissue, are selected. Effects of drugs in the pro-angiogenic and anti-angiogenic factors are incorporated. A plurality of treatment protocols in a protocol space is generated. A best treatment protocol based on a pre-determined criteria is selected.

1. A computer-implemented method for determining an optimal treatment protocol for a disease related to angiogenesis, comprising:
 creating an angiogenesis mathematical model including biological and mathematical parameters and pro-angiogenic and anti-angiogenic components; 
 incorporating effective vessel density (EVD) for regulating switching on and switching off of at least one component in the angiogenesis model; 
 incorporating effects of vasculature maturation and mature vessels destabilization; 
 selecting pro-angiogenic and anti-angiogenic components, which can influence changes in state of a tissue; 
 incorporating effects of drugs in said pro-angiogenic and anti-angiogenic components; 
 generating a plurality of treatment protocols in a protocol space; and 
 selecting a best treatment protocol based on a pre-determined criteria. 
 
   
   
     2. The method of  claim 1 , wherein the model comprises a tissue volume model, an immature vessel model and a mature vessel model. 
   
   
     3. The method of  claim 1 , wherein steps to regulate dynamics which influences EVD are incorporated. 
   
   
     4. The method of  claim 1 , wherein the model simultaneously accounts for tissue cell proliferation, tissue cell death, endothelial cell proliferation, endothelial cell death, immature vessel formation and immature vessel regression, immature vessel maturation and mature vessel destabilization. 
   
   
     5. The method of  claim 1 , wherein the model incorporates temporal parameters that characterize response rate of at least one element associated with angiogenesis. 
   
   
     6. The method of  claim 3 , wherein EVD is calculated by combining immature vessel density and mature vessel density. 
   
   
     7. The method of  claim 1 , wherein parameters incorporated into the model comprises tissue volume, number of free endothelial cells, number of free pericytes, volume of mature vessels, volume of immature vessels and concentration of regulator factors. 
   
   
     8. The method of  claim 7 , wherein the regulatory factors comprise vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2). 
   
   
     9. The method of  claim 3 , wherein EVD is a function of a duration of insufficient perfusion and vice versa. 
   
   
     10. The method of  claim 8  wherein the model incorporates threshold levels of regulatory factors and parameter ratios. 
   
   
     11. The method of  claim 10 , wherein the threshold level is at least one of:
 a) VEGF concentration below which no endothelial cells proliferation takes place (A); 
 b) minimum number of receptors for VEGF above which endothelial cells proliferation takes place (B); 
 c) VEGF concentration below which endothelial cells, both in the free state as well as when incorporated into immature blood vessels, are subject to apoptosis VEGF thr ; 
 d) the minimal number of free pericytes which stimulates the onset of maturation of immature vessels (C); 
 e) Ang 1/Ang 2 ratio below which mature vessels are destabilized, and above which maturation of immature vessels is enabled (K); 
 f) EVD value that influences the rate of cell proliferation; and 
 g) EVD ss  value for which the system is in steady state. 
 
   
   
     12. The method of  claim 11  wherein the tissue volume model calculates the tissue volume by a process comprising:
 i) comparing EVD against an—EVD ss ; 
 ii) if EVD is equal to EVD ss  then using a programmed tissue cell proliferation and a programmed tissue cell death (apoptosis) to compute tissue volume; 
 iii) if EVD>EVD ss  then using increased tissue proliferation and decreased tissue cell death to compute tissue volume; and 
 iv) if EVD<EVD ss  then using decreased tissue proliferation and increased tissue cell death to compute tissue volume. 
 
   
   
     13. The method of  claim 12 , wherein Ang1 and Ang2 induction are incorporated into steps ii, iii and iv prior to compute tissue volume. 
   
   
     14. The method of  claim 13  wherein effects of drugs affecting Ang1 and Ang2 are considered in computing tissue volume. 
   
   
     15. The method of  claim 11  wherein the immature vessel model calculates the immature vessels by a process comprising:
 i) comparing EVD against an EVD ss ; 
 ii) if EVD is equal to EVD ss  then setting VEGF to a VEGF ss  and PDGF to a PDGF ss ; 
 iii) if EVD>EVD ss  then using decreased VEGF and decreased PDGF; and 
 iv) if EVD<EVD ss  then using increased VEGF and increased PDGF; 
 v) comparing VEGF against A; 
 vi) factoring endothelial cell proliferation if VEGF>A; 
 vii) comparing VEGF against a VEGF threshold; 
 viii) factoring free endothelial cell deaths if VEGF>VEGF threshold; 
 ix) comparing VEGF receptor number against B; 
 x) if VEGF receptor number is less than B in step ix then considering no angiogenisis prior to computing immature vessel regression; 
 xi) if VEGF receptor number is not less than B in step ix then computing growth of immature vessels; 
 xii) if VEGF<A then considering no angiogenesis and computing immature vessel regression; 
 xiii) computing immature vessels based on growth immature vessels, immature vessel regression and mature vessel destabilization. 
 
   
   
     16. The method of  claim 15 , wherein immature vessels computation considers no maturation if Ang2/Ang1<K or if number of free pericytes<C. 
   
   
     17. The method of  claim 15 , wherein mature vessel destabilization considers ang1/Tie2 interaction blocking. 
   
   
     18. The method of  claim 17 , wherein no destabilization occurs if Ang2/Ang1>K. 
   
   
     19. The method of  claim 15 , wherein mature vessel model is computed using a procedure comprising:
 i) computing immature vessels; 
 ii) determining if Ang1/Ang2>K; 
 iii) determining if number of free pericytes<C; 
 iv) considering immature vessel maturation if both steps ii and iii are false; and 
 v) factoring no destablization if step ii is false. 
 
   
   
     20. The method of  claim 15  wherein effects of a drug affecting EC proliferation are factored in computing immature vessels. 
   
   
     21. The method of  claim 15  wherein effects of a drug affecting VEGF receptors are factored in computing immature vessels. 
   
   
     22. The method of  claim 16  wherein effects of a drug affecting pericyte proliferation are factored in computing immature vessel computation. 
   
   
     23. The method of  claim 15  wherein effects of a drug affecting VEGF are factored in computing immature vessels. 
   
   
     24. The method of  claim 15  wherein effects of a drug affecting PEGF are factored in computing immature vessel computation. 
   
   
     25. The method of  claim 15  wherein effects of a drug affecting Ang1 are factored in computing immature vessels. 
   
   
     26. The method of  claim 15  wherein effects of a drug affecting Ang2 are factored in computing immature vessel computation. 
   
   
     27. The method of  claim 4 , wherein model takes into account duration of a tissue cell proliferation, tissue cell death, endothelial cell proliferation, endothelial cell death, pericytes proliferation, immature vessel regression, immature vessel maturation and mature vessel destabilization. 
   
   
     28. The method of  claim 7 , wherein model takes into account the duration of VEGF induction, PDGF induction, Ang1 and Ang2 induction by tissue cells and Ang1 and Ang2 induction by endothelial cells. 
   
   
     29. A system for determining an optimal treatment protocol for a disease related to angiogenesis, comprising:
 an angiogenesis mathematical model including biological and mathematical parameters and pro-angiogenic and anti-angiogenic components; 
 a treatment protocol space generator that generates a protocol space of possible treatments for the disease; 
 a treatment selector that selects an optimal protocol, 
 wherein effective vessel density (EVD) regulates switching on and switching off of at least one component in the angiogenesis model; 
 wherein the model incorporates effects of vasculature maturation and mature vessels destabilization; 
 wherein the system is adapted to affect selection of a subset of the pro-angiogenic and anti angiogenic components which can influence changes in state of a tissue and incorporating effects of drugs in the subset of the pro-angiogenic and anti angiogenic components. 
 
   
   
     30. The system of  claim 29 , wherein the model comprises a tissue volume model, an immature vessel model and a mature vessel model. 
   
   
     31. The system of  claim 29 , wherein steps to regulate dynamics which influences EVD are incorporated. 
   
   
     32. The system of  claim 29 , wherein the model simultaneously accounts for tissue cell proliferation, tissue cell death, endothelial cell proliferation, endothelial cell death, immature vessel formation and immature vessel regression. 
   
   
     33. The system of  claim 29 , wherein the model incorporates temporal parameters that characterize response rate of at least one element associated with angiogenesis. 
   
   
     34. The system of  claim 31 , wherein EVD is calculated by combining immature vessel density and mature vessel density. 
   
   
     35. The system of  claim 29 , wherein parameters incorporated into the mode comprises tissue volume, number of free endothelial cells, number of free periciytes, volume of mature vessels, volume of immature vessels and concentration of regulator factors. 
   
   
     36. The system of  claim 35 , wherein the regulatory factors comprise vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2). 
   
   
     37. The system of  claim 31 , wherein EVD is a function of a duration of insufficient perfusion and vice versa. 
   
   
     38. The system of  claim 36  wherein the model incorporates threshold levels of regulatory factors and parameter ratios. 
   
   
     39. The system of  claim 38 , wherein the threshold level is at least one of:
 a) VEGF concentration below which no endothelial cells proliferation takes place (A); 
 b) minimum number of receptors for VEGF above which endothelial cells proliferation takes place (B); 
 c) VEGF concentration below which endothelial cells, both in the free state as well as when incorporated into immature blood vessels, are subject to apoptosis VEGF thr ; 
 d) the minimal number of free pericytes which stimulates the onset of maturation of immature vessels (C); 
 e) Ang 1/Ang 2 ratio below which mature vessels are destabilized, and above which maturation of immature vessels is enabled (K); 
 f) EVD value that influences the rate of cell proliferation; and 
 g) EVDS ss  value for which the system is in steady state. 
 
   
   
     40. A computer program product, including computer-readable media comprising instructions to implement procedures for determining an optimal treatment protocol for a disease related to angiogenesis, said procedure comprising:
 creating an angiogenesis mathematical model including biological and mathematical parameters and pro-angiogenic and anti-angiogenic components; 
 incorporating effective vessel density (EVD) for regulating switching on and switching off of at least one component in the angiogenesis model; 
 incorporating effects of vasculature maturation and mature vessels destabilization; 
 selecting a subset of the pro-angiogenic and anti-angiogenic components, which can influence changes in state of a tissue; 
 incorporating effects of drugs in said subset of the pro-angiogenic and anti-angiogenic components; 
 generating a plurality of treatment protocols space; and 
 selecting a best treatment protocol based on a pre-determined criteria.